Author

Date of Award

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Bradley Olwin

Second Advisor

Jennifer M. Martin

Third Advisor

Robert Garcea

Fourth Advisor

Amy Palmer

Fifth Advisor

Michael Stowell

Abstract

In immunocompromised individuals, B cells infected with Epstein-Barr virus often display tumorigenic growth. One of the viral oncoproteins that contributes to this transformation is the latent membrane protein-1 (LMP-1), which constitutively mimics the signaling of ligand-dependent CD40, a tumor necrosis factor receptor. The experiments described in this dissertation were designed to elucidate the molecular mechanisms that underlie LMP-1's signaling potential. We investigated the relationships between LMP-1's subcellular localization, homo-oligomerization, comigration with detergent-resistant membranes, and its signaling outputs in order to bridge some of the gaps standing in the way of a unified theory of LMP-1 function. The data presented here are consistent with a working model where LMP-1's transmembrane domain drives local homo-oligomerization of small complexes, which in turn are assembled into larger megameric complexes, each with some capacity to perform LMP-1 signaling events. These megameric complexes, or LMP-1-enriched domains (LEDs), create an environment that is either particularly resistant to cholesterol-extraction by MβCD or that has cholesterol-independent DRM-like properties. Upon saturation of this pathway, nascent LMP-1 populates a new subset of juxtanuclear membrane compartments. LED formation is important for proper NFκB signaling and therefore is a promising target for the design of therapeutics against LMP-1-dependent EBV-associated diseases and malignancies.